Transforming growth factor-beta (TGFβ) denotes a superfamily of proteins that includes, for example, TGFβ1, TGFβ2, and TGFβ3, which are pleiotropic modulators of cell growth and differentiation, embryonic and bone development, extracellular matrix formation, hematopoiesis, and immune and inflammatory responses (Roberts and Sporn Handbook of Experimental Pharmacology (1990) 95:419-58; Massague, et al., Ann. Rev. Cell. Biol. (1990) 6:597-646). Other members of this superfamily include activin, inhibin, bone morphogenic protein, and Mullerian inhibiting substance. The members of the TGFβ family initiate intracellular signaling pathways leading ultimately to the expression of genes that regulate the cell cycle, control proliferative responses, or relate to extracellular matrix proteins that mediate outside-in cell signaling, cell adhesion, migration and intercellular communication.
Therefore, inhibitors of the TGFβ intracellular signaling pathway are useful treatments for fibroproliferative diseases. Specifically, fibroproliferative diseases include kidney disorders associated with unregulated TGFβ activity and excessive fibrosis including glomerulonephritis (GN), such as mesangial proliferative GN, immune GN, and crescentic GN. Other renal conditions include diabetic nephropathy, renal interstitial fibrosis, renal fibrosis in transplant patients receiving cyclosporin, and HIV-associated nephropathy. Collagen vascular disorders include progressive systemic sclerosis, polymyositis, scleroderma, dermatomyositis, eosinophilic fascitis, morphea, or those associated with the occurrence of Raynaud's syndrome. Lung fibroses resulting from excessive TGFβ activity include adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, and interstitial pulmonary fibrosis often associated with autoimmune disorders, such as systemic lupus erythematosus and scleroderma, chemical contact, or allergies. Another autoimmune disorder associated with fibroproliferative characteristics is rheumatoid arthritis. Fibroproliferative conditions can be associated with surgical eye procedures. Such procedures include retinal reattachment surgery accompanying proliferative vitreoretinopathy, cataract extraction with intraocular lens implantation, and post glaucoma drainage surgery.
In addition, members of the TGFβ family are associated with the progression of various cancers. M. P. de Caestecker, E. Piek, and A. B. Roberts, J. National Cancer Inst., 92(17), 1388-1402 (2000). For example, it has been found that TGFβ1 inhibits the formation of tumors, probably by inhibition of the proliferation of nontransformed cells. However, once a tumor forms, TGFβ1 promotes the growth of the tumor. N. Dumont and C. L. Arteaga, Breast Cancer Res., Vol. 2, 125-132 (2000). Thus inhibitors of the TGFβ pathway are also useful for the treatment of many forms of cancer, such as lung cancer, skin cancer, and colorectal cancer. In particular, they are useful to treat cancers of the breast, pancreas, and brain, including glioma.
The compounds of the invention herein are derivatives of pyrimidine having an additional ring fused onto the pyrimidine. PCT publication WO01/47921 describes pyrimidine and triazine compounds that are inhibitors of kinase activities associated with various inflammatory conditions, as opposed to the treatment of fibroproliferative disorders described herein. The above mentioned PCT publication describes the use of the disclosed compounds only for treatment of the inflammatory aspects of certain autoimmune diseases. Further, the compounds described differ from those described herein by virtue of the substitutions required on the pyrimidine nucleus; among other distinctions, the compounds disclosed in the PCT publication do not include phenyl bound directly to the pyrimidine ring.
Related compounds, some of which have the 4-pyridylamine group at C-4 on the pyrimidine, are disclosed in two published U.S. patent applications, publications no. US 2004-0132159-A1 and US 2005/0004143-A1. Those applications, however, disclose a preference for certain electron-donating substituents on the pyridine ring of the 4-pyridylamine group, including alkyl, amine and alkoxy groups, and do not disclose a preferred position for substituents. The present invention provides compounds specifically including a 4-pyridylamine containing an essential carboxamide group attached at position 3 on the pyridine ring.
U.S. Pat. No. 6,476,031 also discloses compounds containing a quinazoline ring, which can be a fused bicyclic derivative of a pyrimidine; it includes compounds where the quinazoline ring is linked to an aryl group at C-4 of the quinazoline. The compounds are reported to act at the TGFβ site, and the compounds can include a 4-pyridylamine group as the aryl group linked to the quinazoline at C-4. However, that patent only discloses that a quinazoline compound linked to a pyridyl that is unsubstituted: it does not disclose any compounds with a 4-pyridyl that includes an amide substituent such as the ones at the 3-position of the 4-pyridyl group in the compounds of the present invention.